Abstract The overall objective of this competing R01 application is to discover new peptide motifs that seamlessly encode both lower critical solution temperature (LCST) phase behavior and bioactivity, and to use these new sequences to create the next-generation of LCST polymers with intrinsic biological activity and self- assembled structures with morphological diversity and enhanced stability. The central hypothesis of this proposal is that -contrary to the existing paradigm that only elastin-like polypeptides (ELPs) composed of the canonical VPGXG motif or its close relatives exhibit LCST behavior- there is a vast sequence space of undiscovered amino acid motifs that also display LCST phase behavior upon polymerization. In preliminary studies leading to this proposal, we identified a large and diverse set of peptide motifs that exhibit LCST behavior that depart significantly from the canonical VPGXG motif derived from elastin. We have also identified sequences that simultaneously encode LCST phase behavior and bioactivity, as well as motifs that display different degrees of thermal hysteresis in their soluble-insoluble phase behavior. We plan to build upon these findings by pursuing three inter-related specific aims. In Specific Aim 1, we will synthesize a large set (~65) of different peptide polymers based on the PXnG (n=0 to 4) repeat unit and characterize their LCST phase behavior and their thermal hysteresis. In Specific Aim 2, peptide polymers that display different degrees of thermal hysteresis in their LCST phase behavior will be used to synthesize diblock and triblock copolymers composed of hydrophilic ELP blocks and next-generation hydrophobic polypeptide blocks with different degrees of hysteresis in their LCST phase behaviors. These block copolymers will yield morphologically diverse nanoscale self-assembled structures that display different levels of kinetic stability that is controlled by the hysteresis in the LCST phase behavior of the hydrophobic block. Finally, in Specific Aim 3, from the design rules uncovered in Specific Aim 1 on the sequence level determinants of LCST phase behavior, we will test the hypothesis that bioactive peptides (5-50 amino acids in length) with a partially disordered secondary structure can be reprogrammed into unstructured polymers that display LCST phase transition behavior, while retaining their bioactivity. This Specific Aim will yield -for the first time- peptide polymers wherein the repeat units of the polymers are intrinsically bioactive; by doing so, we will take a major step toward merging the intrinsic biological function of peptides with the useful materials properties of polymers. The significance of this proposal is that it will yield, for the first time, a diverse family of new peptide polymers that display rich LCST phase behavior. The impact of this proposal will be the development of self-assembled structures with tunable stability, as well as the first demonstration that peptide drugs can be converted into stimulus responsive polymers.